The invention relates to delivery of interferon at controlled rates over extended periods of time.
Interferons are a group of glycoprotein cytokines produced by cells in response to various stimuli, such as exposure to virus, bacterium, parasite, or other antigen. Interferons have antiviral, immunomodulatory, and antiproliferative activities. Interferons are classified as Type I or Type II. Interferons classified as Type I bind to a common receptor called the Interferon Type I or α-β receptor and are produced by leukocytes, fibroblasts, or lymphoblasts in response to virus or interferon inducers. Interferon Type I includes interferon alpha (IFN-α), interferon beta (IFN-β), and interferon omega (IFN-ω), but IFN-ω has limited homology to human IFN-α (about 60%) and human IFN-β (about 29%). Interferons classified as Type II are produced by T-lymphocytes. Interferon Type II includes interferon gamma (IFN-γ). Interferons are used for treatment of viral hepatitis, multiple sclerosis, and certain cancers. IFN-ω in particular has been indicated for treatment of Hepatitis B & C populations. The injectable form of IFN-ω is currently in Phase II clinical studies for Hepatitis C. This injectable form is solution-based and is not formulated for sustained delivery.
There is interest in delivering interferons to patients in a controlled manner over a prolonged period without intervention. For instance, sustained delivery of IFN-ω can improve the therapeutic effect of IFN-ω by reduction or elimination of peak plasma-level related effects of multiple bolus injections, thereby potentially minimizing systemic side effects such as fatigue and flu-like symptoms. Sustained delivery of a beneficial agent without intervention can be provided by implantable drug delivery devices, e.g., osmotic, mechanical, or electromechanical pump implants, and depot injections. Implantable drug delivery devices are attractive for a number of reasons. For example, implantable drug delivery devices can be designed to provide therapeutic doses of the drug over periods of weeks, months, or even a year. Depot injections typically provide therapeutic doses over periods of weeks. Implantable drug delivery devices once inserted in the patient are not easily tampered with by the patient. Thus, patient compliance is generally assured.
Sustained delivery of an interferon requires the interferon to be contained within a formulation that is substantially stable at elevated temperature, e.g., 37° C. or higher, over the operational life of the implantable delivery drug device. Interferon is a biomolecular material, specifically a protein. Generally speaking, protein formulations that are stable at elevated temperature for a long duration, e.g., weeks, months, or a year, are difficult to design. Proteins are naturally active in aqueous environments. Therefore, it would be convenient to formulate proteins as aqueous solutions. Unfortunately, proteins are typically only marginally stable in aqueous formulations for a long duration. One reason for this is that proteins can degrade via a number of mechanisms, such as deamidation (usually by hydrolysis), oxidation, disulfide interchange, and racemization, and water is a reactant in many of these degradation pathways. Water also acts as a plasticizer and facilitates denaturation and/or aggregation of protein molecules.
Aqueous protein formulations may be reduced to particles using techniques such as freeze-drying or lyophilization, spray-drying, and desiccation. Such particle protein formulations may exhibit increased stability over time at ambient and even elevated temperature. However, there is the challenge of delivering particle formulations from an implantable drug delivery device at a controlled flow rate. It has been suggested to suspend particle protein formulations in non-aqueous, flowable vehicles to allow their delivery from an implantable drug delivery device. A suitable vehicle typically has a high viscosity, e.g., 1 kP or more, so that the particles can be uniformly dispersed in the suspension for a desired duration.
From the foregoing, there continues to be a need for a formulation of interferon that is stable at storage and delivery conditions for a desired duration and deliverable via an implantable drug delivery device.